Ostwald Ripening Phenomenon
Ostwald ripening (Rawlins 1982; Muller & Bohm 1998) has been described for ultrafine dispersed systems and is responsible for crystal growth, thus increasing the mean diameter of the particle size distribution (PSD). Ostwald ripening is caused by the differences in dissolution solubility between small and large particles. It is in practice an effect based on the higher saturation solubility of very small particles as compared to larger ones. Molecules diffuse from the higher concentrated area around small particles (higher saturation solubility) to areas around larger particles possessing a lower drug concentration. This leads to the formation of a supersaturated solution around the large particles and consequently to drug crystallization and growth of the large particles. The diffusion process of the drug from the small particles to the large particles leaves an area around the small particles that is not saturated any more, consequently leading to dissolution of the drug from the small particles and finally complete disappearance of the small particles. (V. B. Patravale, 2004)
Importance of Ostwald Ripening Phenomenon Control
The presence of this phenomenon, that causes an increase in the mean diameter of the particle size distribution over time, results in an instable behavior of a suspension; therefore, during drying of the suspension (in order to isolate the dry powder), particle size distribution will also tend to shift and, as a consequence, may affect the bioavailability, toxicity and efficacy of the final product.
Current Strategies to Prevent Ostwald Ripening Phenomenon
Typical ways of preventing Ostwald Ripening in suspensions include the addition of stabilizing agents to the original suspension.
WO 2008/013785 discloses a process to stabilize suspensions of solid particles of docetaxel in an aqueous medium using an oil in water emulsion process, where proteins or other polymers are applied as surfactants. The prepared dispersion exhibited little or no particle growth after formation that resulted from Ostwald Ripening. In this document a non-polymeric hydrophobic compound which is substantially insoluble in water is used as an Ostwald Ripening inhibitor.
U.S. Pat. No. 6,749,868 and WO 98/14174 disclose a process to stabilize suspensions of solid particles of paclitaxel by coating them with a protein (that acts like a stabilizing agent) in the absence of conventional surfactants to obtain a stable active pharmaceutical ingredient (API) dispersion with low particle size distributions.
Another example is the usage of three surfactants poloxamer 188: Tween®80 and glycerol used in two different concentrations to stabilize tarazepide particles after homogenization using a wet milling lab scale unit. Stability of the nanosuspensions was found for at least a quarter of a year within an acceptable range and did not change very much within 91 days. (C. Jacobs, 2000)
Additionally US Publication No. 2005/009908 refers to a process for preventing Ostwald Ripening (OR) in particles (particularly in the sub-micron range) in an aqueous medium. This process comprises two steps to produce a stable suspension:                a) Producing a solution of a substantially water insoluble API and an inhibitor in a water miscible organic solvent;        b) Addition of an aqueous phase, comprising water and a stabilizer, precipitating solid particles comprising the inhibitor and the API.        
In this document, the controlled precipitation and the presence of the stabilizing agent are claimed to prevent Ostwald Ripening phenomena in the aqueous medium.
However, stabilizing agents need to be carefully selected in order to assure the desired Ostwald Ripening control. For example ascorbyl palmitate nanocrystals stabilized with Tween® 80 remained in the nanometer size during 3 months of storage at three different temperatures as, on the other hand, this effect was not observed when using sodium dodexyl sulfate (SDS) to stabilize the same particle nanosuspensions. (V. Teeranachaideekul, 2008). Additionally, using these stabilizing agents may not be desirable and/or feasible in all cases; for example, there is a reduced number of excipients approved for inhalation delivery and, even if approved, their addition can impact the aerodynamic performance of the particles, thus affecting the product performance. Based on the earlier approaches that can control Ostwald Ripening without requiring further addition of stabilization agents would be advantageous.
Theoretically particle growth caused by Ostwald Ripening could be eliminated, without the need of stabilization agents, if all the particles in the dispersion had the same size (unimodal distribution) thus improving homogeneity of the particles population (Cornelia M. Keck, et all, 2006); such can be further potentiated by combining this with low solubility of the drug in the anti-solvent, this way keeping the concentration differences sufficiently low to avoid the ripening effect (R. H. Muller, et all, 2001).
U.S. Pat. No. 4,826,689 describes a process to prepare particles with a uniform particle size distribution. This process is carried out by infusing an aqueous precipitating liquid into a solution of the solid in an organic liquid under controlled conditions of temperature and infusion rate, thus controlling the particle size. U.S. Pat. No. 4,997,454 describes a similar process, in which an aqueous or non-aqueous solution is used as a precipitating liquid.
However, in both the earlier cases, the need to isolate the particles as soon as they are produced is mentioned, in order to minimize any particle growth (which may be indicative of the impracticability of true monodisperse distributions and/or of the unavoidable effect of residual solubility). Therefore, in processes which use suspensions in wet media to reduce particle size and which require long residence times, particle growth in the anti-solvent becomes difficult to control or even inevitable.
So far no strategies are reported which are capable of stabilizing the particle size in the presence of Ostwald Ripening without involving immediate isolation of the powder and/or the use of stabilization agents. We have appreciated that it would be desirable to improve on this situation, and have now devised a method which is capable of stabilizing the particle size in the presence of Ostwald Ripening phenomena without any stabilizing agent and without the need to immediately isolate the particles in the form of a powder.